Ps918 Circrna Deregulation in B-cell Pediatric Acute Leukemia: the Mll Recombinome and Beyond
Year: 2019
Type: conference-abstract
Abstract: Background: Activating NOTCH1 mutations are present in approximately 60% of T-cell acute lymphoblastic leukemia (T-ALL) cases. Mutant NOTCH1 is strictly dependent on γ-secretase processing for activation thereby providing a strong rationale for the use of γ-secretase inhibitors (GSIs) as a therapeutic approach for T-ALL. However, available GSI's lead to severe “on-target” gastrointestinal tract, skin and thymus toxicity, limiting their therapeutic application and clinical translation. What is less appreciated is that the enzymatic activity of the γ-secretase complex reflects the combined activity of at least four different complexes. These complexes broadly differ by the inclusion of one of two Presenilin (PSEN) proteins: PSEN1 or PSEN2, providing an opportunity to target specific complexes whilst avoiding toxicity in otherwise healthy tissue. Aims: To determine whether subunit selective gamma secretase inhibition is an effective therapeutic strategy in T-cell acute lymphoblastic leukemia. Methods: RNA-seq analysis was undertaken on T-ALL cell lines and patient samples. To generate mice carrying a Psen1 deletion in all committed B and T cell progenitors, we crossed Psen1 conditional knockout mice with CD2Cre. To generate conditional inducible Psen1 knockout mice, we bred animals harboring the conditional Psen1 allele with Rosa26Cre-ERt2 mice. In vivo bone marrow transplant (BMT) assays were performed using isolated hematopoietic stem and progenitor (HSPCs) cells and transduced with mutant NOTCH1 (HD-mutant, delta PEST) retroviral vectors. T-ALL patient derived xenograft studies in NSG mice were treated daily with MRK-560 (30 μmol/kg) and leukemia burden assessed by bioluminescence and human CD45 staining. Gut toxicity was assessed by Periodic acid–Schiff (PAS) immunohistochemistry. Results: Here we show that PSEN1 is expressed significantly higher than PSEN2 in human T-ALL cell lines and primary T-ALL samples. Genetically, the conditional deletion of Psen1 in mice significantly decreased mutant NOTCH1 receptor processing but did not impair normal T-cell development. Furthermore, specific inducible deletion of Psen1 in a mutant NOTCH1-driven leukemia significantly reduced leukemia burden and increased overall survival in vivo. The significant decrease in leukemic burden identified through genetic loss of Psen1 then prompted us to investigate whether selective pharmacological PSEN1 inhibition would be a viable strategy for T-ALL treatment. To this end, we tested the PSEN1 selective inhibitor MRK-560, which has ∼100-fold selectivity over PSEN2, on four different T-ALL patient-derived xenograft samples with varying NOTCH pathway mutations. MRK-560 monotherapy treatment significantly decreased leukemia burden as measured by in vivo bioluminescence and human CD45 in the peripheral blood and significantly increased overall survival. Moreover, treatment with MRK-560 did not cause any pathological changes in the gastrointestinal architecture nor increased numbers of secretory goblet cells, assessed by Periodic Acid-Schiff (PAS) staining, even after 4 weeks of treatment. Summary/Conclusion: These results demonstrate that inhibition of Presenilin-1 is highly effective in decreasing leukemia whilst avoiding dose-limiting toxicities and that Presenilin-1 selective compounds provide a new therapeutic strategy for safe and effective targeting of T-ALL.
Source: HemaSphere
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,480
OpenAlex ID: W2952391807